Lyophilizing apparatus

ABSTRACT

A lyophilizing apparatus having a refrigeration system including an evaporator section and a condenser section, the evaporator section refrigerating a well-shaped cold trap over which one or more chambers for containing the material to be freeze-dried can be stacked, a source of vacuum in the cold trap subjecting all of the stacked chambers to a low pressure to cause sublimation of the moisture in the material in the chambers and condensation thereof in the cold trap and a means to direct heat given off by the refrigeration condenser against the exterior surface of the chambers and into the same to enhance the sublimation process.

v United States Patent [72) inventor Joseph L. Dantoni Rte 6,Westminster, Md. 21157 [21] Appl. No. 832,701

[22] Filed June 12, 1969 [45] Patented Apr. 13,1971

[54] LYOPHILIZING APPARATUS 3,286,366 11/1966 Seligman .11: 34/5 PrimaryExaminer-William J. Wye Attorneys-J Wesley Everett and George L. BrehmABSTRACT: A lyophilizing apparatus having a refrigeration systemincluding an evaporator section and a condenser section, the evaporatorsection refrigerating a well-shaped cold trap over which one or morechambers for containing the material to be freeze-dried can be stacked,a source of vacuum in the cold trap subjecting all of the stackedchambers to a low pressure to cause sublimation of the moisture in thematerial in the chambers and condensation thereof in the cold trap and ameans to direct heat given off by the refrigeration condenser againstthe exterior surface of the chambers and into the same to enhance thesublimation process.

Patented Aprik 13, 1971 3,574,950

2 Sheets-Sheet 2 INVENTOR LYOPHILIZING APPARATUS This invention relatesto lyophilization or freeze-drying apparatus and more particularly tosuch apparatus which can accommodate both bulk material and material incontainers separately or simultaneously.

ln conventional methods of lyophilization, material is placed incontainers and fast frozen at very low temperatures. The frozen materialis transferred to a vacuum apparatus and moisture is removed bysublimation. Very often heat is applied to the material by use of steam,infrared, or thermal electric devices. Usually the water vapor iscondensed in a cold trap. When the freeze-drying process is complete,the vacuum is broken and the dried material is removed.

Most of the equipment used for lyophilization in the prior art is bulky,complicated, and expensive. Use is frequently made of special types ofcontainers and material must be transferred to several pieces ofapparatus to accomplish the freeze-drying process. Each transfer ofmaterial increases the risk of contamination and very often the processbecomes lengthy. A number of different apparatuses are required, makinglyophilization apparatus very expensive.

it is among the objects of this invention to provide an apparatus inwhich substantially the entire freeze-drying process may be accomplishedwith a minimum of handling and transferring to minimize the possibilityof contamination.

lt is another object to provide an apparatus in which material incontainers may be freeze-dried and sealed or stoppered in a vacuum, inair or in an atmosphere of inert gas.

It is still another object to provide such an apparatus which the heatof the refrigeration machinery may be conveniently utilized to speed thedrying process.

lt is a further object to provide an apparatus of this character inwhich several chambers with material to be freeze-dried may be stackedin communication with each other so that all may be processed at onceand all use the same cold trap and source of vacuum.

The above objects are realized in applicants device by providing anumber of chambers each with sidewalls, preferably of transparentmaterial, such as a plastic Lucite," a bottom also preferably of plasticsealed to the lower edges of the sidewalls, and a sealing ring ofrelatively thick rubberlike material fixedly sealed to the bottom wall.The bottom of each chamber has one or more openings therein to affordcommunication with the interior of the chamber. Any number of suchchambers, within limits, may thus be stacked one upon the other with thesealing ring of each resting in sealing engagement with the uppersidewall edges of the chamber below and the lowermost chamber resting onthe upper edge of the cold trap wall into which a vacuum line extends. Atop plate member with a sealing ring attached is then used to close thetop of the uppermost chamber. All the chambers are thus connected inseries" and are subject to the conditions of vacuum created in the coldwell and the moisture evaporated from materials in each of the chamberswill be conducted to the cold well and there condensed. Various valvedports for introduction of inert gases, air, etc., may be provided forthe chambers through the bases thereof and through the top plate ashereinafter more fully explained.

The objects outlined above and other objects and advantages will becomemore apparent as this description proceeds and reference is had to theaccompanying drawing fonning a part of this specification and in which:

FlG. l is a side view mostly in section of a freeze-drying apparatusincorporating my invention;

FIG. 2 is a sectional view of one chamber provided with a top with meansthereon for closing or stoppering bottles contained therein;

FIG. 3 is a sectional view of a chamber equipped with an externalelectric heater;

FIG. 4 is a sectional view of a chamber equipped with a number of valvesfor attaching vessels, vials and the like to be processed;

FIGS. 5 and 6 are views partly in section showing details of the valvesused in FIG. 4;

FIG. 7 is a sectional view of a chamber with a slightly modified bottom;

FIG. 8 is a sectional view of chamber with a further modified bottomequipped with a depending deflector for the vacuum pipe",

H65. 9 and 10 are sectional views of a form of bottle and stopper suchas may be used to contain material to be treated shown in open andclosed condition respectively.

Referring to the drawing in greater detail and for the present to FIG. 1thereof, 10 represents a cabinet which encloses a refrigeration plant orsystem generally indicated at .11 with the usual condenser portion 12located in one portion 13 of the cabinet and the evaporator or coolingportion 14 located in a second portion 15 of the cabinet. The coolingportion 14 is in the form of a coil wound around the exterior orinterior of a well-like receptacle or cooling trap 16 which is openthrough the top of the cabinet and is there provided with a slightlyraised turned over rim 17 the purpose of which will become apparent asthis description proceeds.

The cold trap 16 is provided with a drain l8 and cutoff valve 19 and asecond pipe 20 extends upwardly through the bottom thereof which, whenthe device is in use, is connected to a source of vacuum, not shown. Thepipe 20 is suitably valved at 21.

The well-like cold trap 16 with its surrounding cooling coil 14 isenclosed in insulating material 22 in the portion 15 of the cabinet toisolate these parts from the outside temperature.

The condenser portion of the refrigeration system is located in thecabinet portion 13 adjacent the insulated evaporator section thereof.The condenser, as is well known, gives off heat and to dissipate thisheat a fan 23 is mounted in the side of the cabinet to force air intothe cabinet portion 13 and out through the top opening 24 thereof.

A hood, generally indicated by 25, is located on the cabinet above theopening 24 and is provided with inclined louvered panels 26 and 27, thelouvers of which may be opened or closed by means of a lever 28 and theymay be so controlled that when the louvers of one panel are closed thoseon the other panel are open so that the heated exhaust air from therefrigeration condenser may be directed in either of two directions. Thepurpose of this construction will be more clearly understood from thedescription that follows.

Chamber members generally indicated 28 are provided for receiving thematerials to be subjected to the freezedrying process. Each chamberconsists of a sidewall portion 29 preferably of transparent plastic suchas Lucite" with a bottom wall 30 also of plastic such as Bakel te sealedto the bottom edges of the sidewalls and a relat vely thick resilientgasket 31 fixed and sealed to the lower surface of the bottom wall. Anopening 32 of fair size through the bottom wall and gasket affordscommunication therethrough.

As may be seen from FIG. 1 a chamber may be placed directly on the rim17 of the cold trap and one or more chambers may be placed or stackedone above the other on the first chamber, the lowermost in sealingengagement with the rim 17 of the cold trap and all the other chambersin sealing engagement with the one below.

The uppermost chamber is closed at its top with a closure plate 33having a sealing gasket 34 attached to its under surface similar to thegaskets 31 on the bottoms of the chambers.

Each chamber is provided with a port 35 extending out wardly through thebottom thereof from the opening 32 to the outside and is there providedwith a stop cock 36 to which a hose may be attached. While thesechambers and other parts are preferably constructed of plastic, anysuitable material may be used.

As previously stated, the condenser section of the refrigeration systemis located adjacent the evaporator section and cold trap. This placesthe hood 25 with its inclined louvers 26 facing the chamber or chambers28 positioned over the cold trap whereby the heat from the condensersection may either be exhausted through the louvers 26 and directedagainst the chambers to assist in the evaporation and sublimation of themoisture contained in the materials in the chambers and it may also beregulated by the lever 28 to exhaust through the louvers 27 or throughboth sets of louvers to regulate the amount of heat thus supplied to thechambers. In addition the amount of heat thus supplied to the chambersthrough regulation of the louvers may be accomplished automatically bythermostatic control if desired.

Provision is also made to supply heated air directly to the interior ofthe chambers through the pipe 37 leading from the interior of thecondenser section of the cabinet through a control valve 38 and hose 39to the port 40 in the top plate 33 closing the uppermost chamber. Forconvenience in closing off the port 40 when interior heating is not useda valve 41 may be used.

Flow of heated air into the chambers may be automatically regulated, ifdesired, by providing a thermostatic valve 42 in the line 39 controlledfrom a sensing device 43 inserted into the chamber through the top plate33.

The operation of the apparatus shown in FIG. 1 is as follows: With therefrigeration machinery in operation one or several of the chambers 28containing the prefrozen materials to be lyophilized are. placed overthe cold trap in stacked relation and a cover plate 33 is placed overthe uppermost chamber. The pipe through its valve 21 is then connectedto a source of vacuum. This will subject the interiors of the chambersto a very low pressure and will cause the frozen materials to beginlosing moisture by sublimation. The moisture will be drawn into the coldtrap and there condensed and frozen on the low temperature walls of thecold trap. This process will continue until all the moisture has beenextracted from the materials being processed, after which the source ofvacuum may be cutoff and the dried materials removed from the chambers.

It may be desirable under certain circumstances to heat the chambersduring the drying process to speed evaporation. With the instant devicethis may be accomplished by opening the louvers 26 to direct the heatedair from the refrigeration condenser toward and against the chambers orheated air may be introduced directly into the chambers through thepipes 37 and 39 by opening the valves 38 and 41. The sensor 43 acting onthermostatic valve 42 may then be used to control the amount of heat tosuit the particular conditions.

In addition the freeze-drying process may be effected in an atmosphereof inert gas such as nitrogen or sterile air by connecting a source ofsupply of such gases through the valved ports 35 and 36 in the chambers.

It should be noted that the vacuum pipe 20 is provided with a deflectoror hood 44 for the purpose of preventing entry into the vacuum pipe ofmoisture and ice crystals and thus avoid clogging and damage to thevacuum system.

After completion of the freeze-drying run the refrigeration system is,of course, shutdown and the frozen moisture in the cold well allowed tomelt whereupon it may be drained off through pipe 18 by opening thevalve 19.

The device shown in FIG. 2 is one means whereby a number of bottlescontaining material to be lyophilized may be stoppered while still undervacuum and enclosed in a chamber. A special top plate 45 adapted to fitany of the chambers 28 is employed. This top plate is provided with asealing gasket 46 on its lower surface and a central opening 47 throughwhich a reciprocatory rod 48 extends. A piston 49 is mounted on thelower end of the rod and is slidable on the inner surface of the chamberand is sealed against leakage by means of O-rings or the like 50. Theupper end of the rod 48 extends above the top plate and a suitable lever51 and ratchet arrangement 52 mounted on the top plate may be employedto propel the rod and piston downwardly. As an alternative means formoving the piston, the top plate is provided with a port 53 and stopcock 54 for attachment to a source of pressure to force the pistondownwardly.

In using the device shown in FIG. 2 bottles 55 containing the materialto be freeze-dried are employed. These bottles are equipped withstoppers 56 which have depending leg portions 57 leaving open side ports58 when the stoppers are not pressed fully down as shown in detail inFIG. 9 but which fully seal the bottles when pressed down. The bottlesand contents with their stoppers in the position shown in FIG. 9 areplaced in the chamber for processing, the open side ports 58 enablingthe contents to be subjected to conditions within the chamber. Aftercompletion of the drying process the stoppers are pressed to closedposition by the piston 49. These chambers may in many instances carry aninert gas such as nitrogen which may be introduced through the valve 36.

FIG. 3 shows a modified form of chamber which, for all intents andpurposes, is substantially similar to those shown in FIG. 1 except thatan external electric heating element 59 surrounds the sidewall 29 whichmay be used in lieu of or in combination with the above-mentionedheating means to enhance the evaporation process. This heater may becontrolled by a suitable thermostatic switch 60 if desired.

FIG. 3 also shows a rack or shelf device 61 for holding several rows ofbottles or containers which may be used in any of the chambers shown.

FIG. 4 shows a chamber with sidewalls 29 equipped with a plurality ofoutlets to which bottles or vials 62 may be attached for processing thecontents thereof. Each outlet (see FIGS. 5 and 6 for details) consistsof a nipple 63 sealed in the sidewall 29' and having an axial passage 64therein in communication with the interior of the chamber, and a lateralport 65 near the end thereof communicating with the axial passage. A capmember 66 of rubber or resilient plasticlike material is fittedrotatably on the end of the nipple and is provided with a diagonallypositioned hollow branch 67 which in one position of rotation willregister with the port 65 to open the valve, and in another position beout of registry with the port to close the valve. The bottles or vialsto be processed may be directly connected to the branches 67 as seen inFIG. 5.

The top 33, 34 utilized with the chamber shown in FIG. 4 is duplicate ofthat shown in FIGS. 1 and 4, while the bottom 30', 31' is similar tothat shown in FIGS. 1 and 4 except that the opening in the center isprovided with an inserted thimble 68 which projects upwardly somewhatfrom the interior bottom surface and forms a flange about the openings,and the port 35 and valve 36 shown in FIGS. 1 and 4 are not provided.

FIG. 7 is a modified form of chamber in which the bottom wall 30" andgasket 31" are provided with a plurality of small openings 69 in lieu ofa single large opening as shown in FIGS. 1 and 4. The sidewalls 29 andtop plate 33, 34 are identical to those in FIGS. I and 4.

FIG. 8 is also a modification but is very similar to that of FIG. 7except that it is equipped centrally of its bottom with a removabledepending stem 70 which carries at its lower extremity a deflector 71which may be used in place of the deflector 44 previously described.Small openings 69' are used in this form similar to the small openings69 in the form shown in F IG. 7. I

It is to be understood that the forms of chambers shown in FIGS. 2, 3and 4 are shown in position directly over the cold trap, they may alsobe used in stacked arrangement over other chambers if desired.

Iclaim:

I. A lyophilizing apparatus comprising:

a. a refrigeration apparatus having an evaporator section and acondenser section, the evaporator section refrigerating a moisturecondensing cold trap, and the condenser section having a heatdissipating means;

b. a source of vacuum in said cold trap;

c. at least one enclosed chamber member adapted to contain the materialto be freeze-dried positioned over said cold trap with its interior incommunication therewith and with the source of vacuum therein wherebythe interior of said chamber with its contained material is subjected tothe low pressure of said vacuum source to cause sublimation of themoisture contained in said material and conduction thereof to said coldtrap to be condensed therein; and d. means to direct the heat dissipatedby said condenser section against said chamber to enhance thesublimation process.

2. The structure defined in claim 1 in which a plurality of chambers arestacked one upon the other in sealing engagement with each other andinteriorly communicating with each other whereby all of the chambers aresubjected to the low pressure in said cold trap.

3. The structure defined in claim 1 in which the means to direct theheat dissipated from said condenser section comprises a hood disposedover said condenser section, said hood having an inclined panel withlouvers facing the chamber and a means to force the air from saidcondenser section through said louvers and against the outer surface ofsaid chamber to heat the same.

4. The structure defined in claim 1 in which the means to direct theheat dissipated from said condenser section comprises a duct incommunication with said condenser section said duct connected to and incommunication with the interior of Said chamber and means to force theair from said condenser section through said duct and into the chamberto heat the same.

5. The structure defined in claim 3 in which the hood is provided with asecond inclined panel with louvers facing in a direction opposite saidfirst. panel and away from said chamber, the louvers of both panelsprovided with means to open and close the same whereby the amount of airemitted through the louvers ofboth panels may be controlled. 6. Thestructure defined in claim 1 in which the chamber comprises sidewalls, abottom wall sealed to the bottom edges of said sidewalls, said bottomwall having at least one opening therethrough, a sealing means adheredto said bottom wall for sealing engagement with said cold trap and a topplate having a sealing means on its under surface for sealingly engagingthe upper edges of said sidewalls.

7. The structure defined in claim 6 in which the bottom wall has a portextending from the interior of said chamber to the exterior thereof anda valvein said port.

8. The structure defined in claim 6 in which an electric heating elementsurrounds said sidewalls.

9. The structure defined in claim 6 in which said top plate is providedwith a piston rod extending therethrough, a piston on the lower end ofthe piston rod adapted to slidably engage the interior surface of saidsidewalls and means to propel said piston downwardly in said chamber.

10. The structure defined in claim 6 in which the sidewalls of thechamber are provided with a plurality of radially extending hollownipples communicating with the interior of said chamber, each saidnipple having a lateral port near the outer end thereof, a cap ofresilient material rotatably mounted on each nipple and having a tubeextending laterally therefrom which by rotation of the cap maybe broughtinto registry with said lateral port or out of registry therewith, saidlateral tube adapted to receive and hold a bottle.

11. A lyophilizing apparatus comprising:

a. a refrigeration apparatus having an evaporator section and acondenser section, the evaporator section refrigerating a moisturecondensing cold trap, and the condenser section having a heatdissipating means;

b. a source of vacuum in said cold trap;

c. at least one enclosed chamber member positioned over said cold trapwith 'its interior in communication therewith and with the source ofvacuum therein whereby the interior of said chamber is subjected to thelow pressure of said vacuum source, at least one container in saidchamber containing the material to be freeze-dried whereby saidcontainer with its contained material will be subjected to the lowpressure of said vacuum source to cause sublimation of the moisturecontained therein; and

d. means for supplying a predetennined amount of heat from the condensersection to the material to be freezedried while the said chamber issubiected to low pressure. 12. A structure defined in claim 11 Withmeans to introduce into said chamber while the chamber is subjected tothe low pressure vacuum and means for sealing the material in saidcontainer prior to releasing the said vacuum in said chamber.

2. The structure defined in claim 1 in which a plurality of chambers arestacked one upon the other in sealing engagement with each other andinteriorly communicating with each other whereby all of the chambers aresubjected to the low pressure in said cold trap.
 3. The structuredefined in claim 1 in which the means to direct the heat dissipated fromsaid condenser section comprises a hood disposed over said condensersection, said hood having an inclined panel with louvers facing thechamber and a means to force the air from said condenser section throughsaid louvers and against the outer surface of said chamber to heat thesame.
 4. The structure defined in claim 1 in which the means to directthe heat dissipated from said condenser section comprises a duct incommunication with said condenser section said duct connected to and incommunication with the interior of said chamber and means to force theair from said condenser section through said duct and into the chamberto heat the same.
 5. The structure defined in claim 3 in which the hoodis provided with a second inclined panel with louvers facing in adirection opposite said first panel and away from said chamber, thelouvers of both panels provided with means to open and close the samewhereby the amount of air emitted through the louvers of both panels maybe controlled.
 6. The structure defined in claim 1 in which the chambercomprises sidewalls, a bottom wall sealed to the bottom edges of saidsidewalls, said bottom wall having at least one opening therethrough, asealing means adhered to said bottom wall for sealing engagement withsaid cold trap and a top plate having a sealing means on its undersurface for sealingly engaging the upper edges of said sidewalls.
 7. Thestructure defined in claim 6 in which the bottom wall has a portextending from the interior of said chamber to the exterior thereof anda valve in said port.
 8. The structure defined in claim 6 in which anelectric heating element surrounds said sidewalls.
 9. The structuredefined in claim 6 in which said top plate is provided with a piston rodextending therethrough, a piSton on the lower end of the piston rodadapted to slidably engage the interior surface of said sidewalls andmeans to propel said piston downwardly in said chamber.
 10. Thestructure defined in claim 6 in which the sidewalls of the chamber areprovided with a plurality of radially extending hollow nipplescommunicating with the interior of said chamber, each said nipple havinga lateral port near the outer end thereof, a cap of resilient materialrotatably mounted on each nipple and having a tube extending laterallytherefrom which by rotation of the cap may be brought into registry withsaid lateral port or out of registry therewith, said lateral tubeadapted to receive and hold a bottle.
 11. A lyophilizing apparatuscomprising: a. a refrigeration apparatus having an evaporator sectionand a condenser section, the evaporator section refrigerating a moisturecondensing cold trap, and the condenser section having a heatdissipating means; b. a source of vacuum in said cold trap; c. at leastone enclosed chamber member positioned over said cold trap with itsinterior in communication therewith and with the source of vacuumtherein whereby the interior of said chamber is subjected to the lowpressure of said vacuum source, at least one container in said chambercontaining the material to be freeze-dried whereby said container withits contained material will be subjected to the low pressure of saidvacuum source to cause sublimation of the moisture contained therein;and d. means for supplying a predetermined amount of heat from thecondenser section to the material to be freeze-dried while the saidchamber is subjected to low pressure.
 12. A structure defined in claim11 with means to introduce into said chamber while the chamber issubjected to the low pressure vacuum and means for sealing the materialin said container prior to releasing the said vacuum in said chamber.